Comparison of three radioligands for the labelling of human β-adrenoceptor subtypes

We have compared the ability of three radioligands, [¹²⁵I]-cyanopindolol, [³H]-CGP 12,177 and [³H]-dihydroalprenolol, to label the three human β-adrenoceptor subtypes. Saturation and competition binding experiments were performed using membrane preparations from Chinese hamster ovary cells stably transfected with the three subtypes. While [³H]-CGP 12,177 had very similar affinity for β₁- and β₂-adrenoceptors (about 40 pM), [¹²⁵I]-cyanopindolol and [³H]-dihydroalprenolol had 4- to 6-fold higher affinity for β₂- as compared to β₁-adrenoceptors (10 vs 45 and 187 vs 1,021 pM, respectively). The affinity of [¹²⁵I]-cyanopindolol at β₃-adrenoceptors was considerably lower (440 pM) than at the other two subtypes. The β₃-adrenoceptor affinity of [³H]-CGP 12,177 and [³H]-dihydroalprenolol was so low that it could not be estimated within the tested range of radioligand concentrations (up to 4,000 pM and 30,000 pM for [³H]-CGP 12,177 and [³H]-dihydroalprenolol, respectively). We conclude that all three radioligands are ill-suited to label β₃-adrenoceptors, particularly in preparations co-expressing multiple subtypes. In the absence of alternatives, [¹²⁵I]-cyanopindolol appears the least unsuitable to label β₃-adrenoceptors. There is a need for high-affinity radioligands which are either selective for β₃-adrenoceptors or reasonably non-selective among all three β-adrenoceptor subtypes.     

Ammonia affects brain nitrogen metabolism but not hydration status in the Gulf toadfish (Opsanus beta)

Laboratory rodents made hyperammonemic by infusing ammonia into the blood show symptoms of brain cell swelling and increased intracranial pressure. These symptoms could be caused in part by an increase in brain glutamine formed when brain glutamine synthetase (GS) naturally detoxifies ammonia to glutamine. Previous studies on the Gulf toadfish (Opsanus beta) demonstrated that it is resistant to high ammonia exposure (HAE) (96 h LC(50)=10mM) despite an increase in brain glutamine. This study attempts to resolve whether the resistance of O. beta is mediated by special handling of brain water in the face of changing glutamine concentrations. Methionine sulfoximine (MSO), an inhibitor of GS, was used to pharmacologically manipulate glutamine concentrations, and magnetic resonance imaging (MRI) was used to assess the status of brain water. Ammonia or MSO treatment did not substantially affect blood acid-base parameters. Exposure to 3.5mM ammonium chloride in seawater for 16 or 40 h resulted in a parallel increase in brain ammonia (3-fold) and glutamine (2-fold) and a decrease in brain glutamate (1.3-fold). Pre-treatment with MSO prevented ammonia-induced changes in glutamine and glutamate concentrations. HAE also induced an increase in plasma osmolality (by 7%) which was probably due to a disturbance of osmoregulatory processes but which did not result in broader whole body dehydration as indicated by muscle water analysis. The increase in brain glutamine was not associated with any changes in brain water in toadfish exposed to 3.5 mM ammonia for up to 40 h or even at 10, 20 and 30 mM ammonia consecutively and for one hour in each concentration. The lack of brain water accumulation implies that ammonia toxicity in toadfish appears to be via pathways other than cerebral swelling. Furthermore, toadfish pre-treated with MSO did not survive a normally sub-lethal exposure to 3.5 mM ammonia for 40 h. The enhancement of ammonia toxicity by MSO suggests that GS function is critical to ammonia tolerance in this species.     

The Effects of Introducing Mixed Payment Systems for Physicians: Experimental Evidence

Mixed payment systems have become a prominent alternative to paying physicians through fee‐for‐service and capitation. While theory shows mixed payment systems to be superior, causal effects on physicians' behavior when introducing mixed systems are not well understood empirically. We systematically analyze the influence of fee‐for‐service, capitation, and mixed payment systems on physicians' service provision. In a controlled laboratory setting, we implement an exogenous variation of the payment method. Medical and non‐medical students in the role of physicians in the lab (N = 213) choose quantities of medical services affecting patients' health outside the lab. Behavioral data reveal significant overprovision of medical services under fee‐for‐service and significant underprovision under capitation, although less than predicted when assuming profit maximization. Introducing mixed payment systems significantly reduces deviations from patient‐optimal treatment. Although medical students tend to be more patient regarding, our results hold for both medical and non‐medical students. Responses to incentive systems can be explained by a behavioral model capturing individual altruism. In particular, we find support that altruism plays a role in service provision and can partially mitigate agency problems, but altruism is heterogeneous in the population. Copyright © 2015 John Wiley & Sons, Ltd.     

Treatment of Patients with Early Breast Cancer: Evidence,Controversies, Consensus: German Expert Opinions on the 17th International St. Gallen Consensus Conference

This yearʼs 17th St. Gallen (SG) Consensus Conference on the Treatment of Patients with Early Breast Cancer (SG-BCC) with the title “Customizing local and systemic therapies for women with early breast cancer” focused on the challenge of targeting the treatment of early breast cancer more specifically to the individual disease situation of each patient. As in previous years, a German working group of leading breast cancer experts discussed the results of the international SG-BCC 2021 in the context of the German guideline. It is helpful to compare the SG recommendations with the recently updated treatment recommendations of the Breast Commission of the German Working Group on Gynaecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie e. V., AGO) and the S3 guideline because the SG-BCC panel comprised experts from different countries, which is why country-specific aspects can be incorporated into the SG recommendations. The German treatment recommendations of the AGO and the S3 guideline are based on current evidence. Nevertheless, any therapeutic decision must always undergo a risk-benefit analysis for the specific situation and to be discussed with the patient.Key words: St. Gallen Consensus 2021, early breast cancer, surgery, radiotherapy, (neo)adjuvant systemic therapy, targeted therapy     

Sensor-operated faucets: a possible source of nosocomial infection?

Recently, contamination of sensor-operated faucets (SOFs) with Pseudomonas aeruginosa was observed. To evaluate odds ratios, we conducted a case-control study in which handle-operated faucets served as controls. No statistically significant difference in P. aeruginosa counts was observed between SOFs and regular faucets in our study (odds ratio, 0.0; 95% confidence interval, 0.0 to 39.0; two-sided P exact = .99).     

The Regulatory Effect of Histamine on the in Vitro Synthesis of IgE

The effect of histamine and its H1 and H2 antagonists, chlorpheniramine and cimetidine, on the in vitro, PWM-induced, synthesis of IgG and IgE was studied. Histamine had no effect, and cimetidine had a slight inhibitory action. In contrast, chlorpheniramine induced marked suppression of both IgE and IgG synthesis. This effect could not be attributed to drug-induced cytotoxicity. These results suggest that the modulatory effect of histamine on antibody production involves predominantly H1 receptors.     

Fitz-Hugh-Curtis syndrome: a diagnosis to consider in women with right upper quadrant pain

Fitz-Hugh-Curtis syndrome--inflammation of the liver capsule associated with genital tract infection--occurs in up to one fourth of patients with pelvic inflammatory disease (PID). Classically presenting as sharp, pleuritic right upper quadrant pain, usually but not always accompanied by signs of salpingitis, it can mimic many other common disorders such as cholecystitis and pyelonephritis.     

Prediction of specific pathogens in patients with sepsis: evaluation of TREAT, a computerized decision support system

BACKGROUND: Prediction of bacterial infections and their pathogens allows for early, directed investigation and treatment. We assessed the ability of TREAT, a computerized decision support system, to predict specific pathogens. METHODS: TREAT uses data available within the first few hours of infection presentation in a causal probabilistic network to predict sites of infection and specific pathogens. We included 3529 patients (920 with microbiologically documented infections) participating in the observational and interventional trials of the TREAT system in Israel, Germany and Italy. Discriminatory performance of TREAT to predict individual pathogens was expressed by the AUC with 95% confidence intervals. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit statistic. RESULTS: The AUCs for Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. and Escherichia coli, ranged between 0.70 and 0.80 (all significant). Adequate calibration was demonstrated for any Gram-negative infection and individual bacteria, except for E. coli. Discrimination and calibration were acceptable for Enterococcus spp. (AUC 0.71, 0.65-0.78), but not for Staphylococcus aureus (AUC 0.63, 0.55-0.71). The few infections caused by Candida spp. and Clostridium difficile were well predicted (AUCs 0.74, 0.54-0.95; and 0.94, 0.88-1.00, respectively). The coverage with TREAT's recommendation exceeded that observed with physicians' treatment for all pathogens, except Candida spp. CONCLUSIONS: TREAT predicted individual pathogens causing infection well. Prediction of S. aureus was inferior to that observed with other pathogens. TREAT can be used to triage patients by the risk for specific pathogens. The system's predictions enable it to prescribe appropriate antibiotic treatment prior to pathogen identification.